5-nitro-furyl-(2)-methylidene hydrazides



United States Patent 12 Claims. (Cl. 260-240) The present invention provides 5-nitrofuryl-(2)-methylidene hydrazides of monocyclic, six-membered diazine carboxylic acids whose ring nitrogen atoms are separated by at most 1 carbon atom, if desired of their quaternary ammonium derivatives and salts thereof, and a process for their preparation.

As diazine-carboxylic acids of the above-defined type pyridazine or pyrimidine carboxylic acids are especially suitable and their derivatives whose nuclei are wholly or partially hydrogenated.

A special object of the invention is the manufacture of pyridazine-carboxylic acid-N'-[S-nitrofuryl-(Z)-methylidene]-hydrazides, of their derivatives whose hetero nucleus is wholly or partially hydrogenated, if desired of their quaternary ammonium derivatives and of salts thereof. In these compounds the carboxylic acid hydrazide group is preferably attached to a carbon atom of the hetero nucleus, above all in position 3 of the pyridazine ring.

The new compounds may be substituted in any desired manner. More especially the heterocyclic nucleus may contain further substituents; primarily, it may be N-substituted and/or C-substituted, for example by unsubstituted or substituted hydrocarbon radicals, or by saturated or unsaturated heterocyclic or heterocyclic aliphatic groups.

Hydrocarbon radicals are, for example, saturated or unsaturated aliphatic, alicyclic, alicyclic-aliphatic, arali phatic or aromatic hydrocarbon radicals, such as lower straight or branched alkyl or alkenyl radicals, for example methyl, ethyl, propyl, isopropyl, straight or branched radicals linked in any desired position, being butyl, pentyl, hexyl or heptyl, allyl or methallyl radicals, cycloalkyl or cycloallcenyl radicals such as cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl radicals, cycloalkylor -alkenyl-alkyl radicals, such as cyclopentylor cyclohexenyl-methyl, -ethyl or -propyl radicals, aralkylor aralkenylsuch as phenyl-methyl, -ethyl, -vinyl or -propyl radicals or aryl radicals, more especially phenyl radicals. Suitable heterocyclic or heterocyclic-aliphatic radicals are above all mono-nuclear ones, such as (if desired wholly or partially hydrogenated) pyridyl, pyrimidyl, pyridazyl, pyrazyl, furyl or thienyl groups and corresponding heterocyclyl-alkyl radicals, such as pyridyl-, furyl-, or thienyl-methyl or -ethyl radicals.

As substituents of the aforementioned aliphatic radicals there may be mentioned more especially free or substituted hydroxyl, mereapto or amino groups in which the substituents are preferably of aliphatic nature, for example lower alkoxy, alkylmercapto or monoor dialkylor cycloalkyl-amino groups, alkyleneamino, oxaallcyleneamino, azaalkyleneamino or thialkyleneamino groups, such as methyl-, ethyl-, propyl-, butyl-, pentylor hexyl-oxy or -mercapto groups, methyl-, dimethy1-, ethyl-, diethyl-, propyl-, dipropyl-, N-methyl-N-propyl-, N-methyl-N-cyclopropyl-, butyl-, dibutyl-amino groups, pyrrolidino, piperidino, morpholino or piperazino groups, for example the piperazino, N-methylpiperazino or N-hydroxyethyl-piperazino group, or a corresponding aminoalkylamino group.

,in the manner described above.

3,234,219 Patented Feb. 8, 1966 The aliphatic radicals may also be substituted by halogen atoms such as chlorine, bromine or iodine, the pseudohalogen trifluoromethyl, nitr'o groups, free or functionally converted carboxyl groups such as cyano, carbalkoxy or carbamyl groups, guanidiuo, ureido or thioureido groups, oxo, thiono or imino groups.

The alicyclic radicals may contain above all lower alkyl radicals.

Aromatic or heterocyclic radicals may contain above all halogen atoms or the above mentioned free or sub? stituted hydroxyl, mercapto or amino groups, alkylor alkylenedioxy, nitro groups or free or converted carboxyl groups. In the alicyclic-aliphatic, araliphatic and heterocyclic-aliphatic radicals both components may be substituted as described above.

When an oxo group is attached to the a-carbon atom of a substituting radical, the radical is that of a carboxylic acid, above all of a lower fatty acid, aralkane-carboxylic acid, heterocyclyl-alkane-carboxylic acid, aromatic or heterocyclic carboxylic acids which may be substituted Particular mention deserve the acetic, propionic or butyric acid or substituted or unsubstituted benzoic or phenylacetic acids.

The heterocyclic nuclei which may be hydrogenated may be further C-substituted, for example by halogen atoms, nitro, nitroso, free or substituted hydroxyl, mercapto or amino groups or free or functionally converted carboxyl groups, oxo, thiono or imino groups such, for example as those mentioned above or by a further carboxylic acid-N'-[5-nitrofuryl-( 2)-methylidene]-hydrazide group.

Finally, the new compounds may also be substituted for example at the hydrazide nitrogen, above all by one of the aforementioned substituted or unsubstituted hydrocarbon or heterocyclic groups, more especially by alkyl. Quaternary ammonium derivatives are above all the alkyl or benzyl ammonium compounds of tertiary bases.

Suitable pyridazine-carboxylic acids are especially those of the formula (iJOOB in which R represents a hydrogen or halogen atom or an;

aryl or allroxy group or a tertiary aminoalkoxy; group,

tioned above; or those of the formula HOOC I formula l nooc I i in which R .or R have the meaning defined in the preceding formula, and R represents a halogen atom or a free or etherified hydroxyl group, for example an alkoxy or tertiary amino-alkoxy, or a free or substituted amino group such for example as those mentioned above; or those of the formula COOH Pyridazine 3-carboxylic acid, 6-phenylpyridazine-3-carboxylic acid, 3-phenyl-6-pyridazone-5-ca;rboxylic acid, 6-pyridazone-3-carboxylic acid,

6-methoxy-, ethoxyor propoxy-pyrid-azine-3-carboxylic acid,

6-(fi-dimethylamino-, dimethylamino-, pyrro1idino-, morpholino-, piperidinoor piperazino-ethoxy)-pyridazine- 3-carboxylic acid, pyridazine-4-carboxylic acid, 3:6-bis-(B-diethylamino dimethylamino-, pyrrolidino-,

morpholino-, piperidinoor piperazino-ethoxy)-pyridazine-4-carboxylic acid, 3:6-bis-methoxy-, ethoxyor boxylic acid,

Pyridazine-3 6-dicarhoxylic acid,

5 6-diphenylpyridazone-(3 )-4-carboxylic acid,

2:5 :6-triphenylpyridazone-(3)-4-carboxylic acid,

5 6-dimethylpyridazone-( 3 )-4-carboxylic acid,

S-phenyl-6-methy1pyridazone-( 3 -4-carboxylic acid,

5 6-di-para-chlorophenylpyridazone-( 3 -4-carboxylic acid,

5:6-cyclohexanopyridazone-(3,)-4-carboxylic acid,

2: 5 6-trimethylpyridazone-( 3 )-4-carboxylic acid,

Z-rnethyI-S 6-diphenylpyridazone-( 3 -4-carboxylic acid,

2 methyl-5:6-di-para-chlorophenylpyridazone-(3)-4-carboxylic acid,

3-pyridazone-4 carboxylic acid,

2-methylpyridazone-(3)-4-carboxylic acid,

2-ethyl-5 6 -dimethylpyridazone-( 3 -4-carboxylic acid,

2 6-dimethyl-S-phenylpyridazone- 3 )-4-ca rboxylic acid,

2-(fi-dimethylamino-, diethylamino-, pyrrolidino-, piperidino-, morpholino-, piperazino-ethyl)-5:6-H, dimethylor diphenyl-pyridazone-(3)-4-carboxylic acid,

3:4-H or dimethyl-6-chloropyridazine-5;carboxylic acid,

3 :4-diphenyl-6-chloropyridazine-5-carboxylic acid,

3:4-H, dimethylor diphenyl-6-methoxy-, ethoxy-, di-

methylamino-, diethylamino-, pyrrolidino-, piperidino-, morpholino-, piperazino-pyridazine-5-carboxylic acid, or

3:4-H, methylor phenyl-6-(B-diethylamino-, dimethylamino-, pyrrolidino-, morpholino-, piperidinoor piperazino-ethoxy)-pyridazine-5-carboxylic acid,

1-phenyl-, halogenophenyl-, nitrophenyl-, pyridyl-(2)-6- methylor -ethyl-pyridazone-(4)-3-carboxylic acid.

propoxy-pyridazine-4-car- 4 A As pyrimidine-carboxylic acids may be mentioned, for example, those of the formula in which R, R and R represent free or substituted hydroxyl, amino or mercapto groups, for example as indicated above, hydrogen, halogen atoms or lower alkyl radicals, or those of the formula (IJOOH in which R, R and R stand for hydrogen or lower alkyl radicals. Examples of such acids are pyrimidine-tearboxylic acid, 5-methyl-pyrimidine-4-carboxylic acid, 6- methyl pyrimidine 4-carboxylic acid, pyrimidine-S-carboxylic acid, orotic acid, 2:4-diamino-pyrimidine-5-carboxylic acids, 2-hydroxy-4-amino-pyrimidine-S-carboxylic acids, 2:4-diamino-pyrimidine-6-carboxylic acids and, if desired, their N-substitution products.

The new compounds display a valuable antibacterial action, more especially towards cocci. They are also effective against trypanosomes, trichomonads or amoebae. They can therefore be used as chemotherapeuticals, for example for treating streptococcal, staphylococcal or protozoan infections in animals or humans. They are also active against colibacteria and can be used as urinedisinfectants. They can also be used as intermediates for the manufacture of medicaments.

Especially valuable are compounds of the formula III-R more especially a dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino group. The phenyl or benzyl radicalsmay contain lower alkoxy, alkylmercapto, alkyl-, alkylenedioxy groups and/or halogen atoms. Of special value among these compounds are those of the formula and their salts. In this formula N=B represents a lower dialkylamino, morpholino, piperazino, pyrrolidino or piperidino group; n=2 or 3. Special mention deserve 1 (fi-diethylaminoethyl)-6-oxo-1:6-dihydropyridazine-3- carboxylic acid-(5'-nitro-2'-furfurylidene)-hydrazide and When a resulting compound per se. Advantageously a hydrazide of a monocyclic six membered diazine carboxylic acid whose ring nitrogen atoms are separated by at most 1 carbon atom is condensed with a S-nitrofuran- (2)-carbonyl compound, more especially with S-nitrofuran-Z-aldehyde, to form the hydrazone. This condensation is likewise carried out in the usual manner, and the carbonyl group may also be in a reactively converted form. Thus it is possible to use, for example, acetals, thioacetals, oximes,-bisulphite compounds or acylates of the carbonyl compounds.

The aforementioned reaction is preferably carried out in the presence of diluents, and with heating.

The starting materials are known or, inasmuch as they are new, can be made by methods known per se. If desired, they may be used in the form of salts thereof. 1 tertiary aminoalkyl-6-oxo-l:6-dihydropyridazine-3-carboxylic acid hydrazides, Z-amino or Z-aminoalkyl-aminw 4 hydroxy or amino-pyrimidine-S-carboxylic acid hydrazides as well as their salts, are new and form another object of the present invention. They are obtained in the usual manner, for example by reacting a suitable carboxylic acid or a reactive derivative thereof with hydrazine. The other new starting materials likewise form an object of the invention.

Depending on the reaction conditions and starting materials used the new compounds are obtained in the free form or in the form of salts thereof. The salts of the new compounds can be converted in the known manher into the free compounds, acid addition salts, for example, by reaction with a basic agent, or a'metal salt if desired by reaction with an acid. On the other hand, a resulting acid compound can be converted into a salt by treatment with a basic agent, for example with a hydroxide or carbonate of an alkali metal such as sodium hydroxide or potassium carbonate; or a resulting free base on the other hand can be made into a salt with an inorganic or organic acid. Acid addition salts are advantageously prepared with therapeutically useful acids, for example hydrohalic acids, for example hydrochloric or hydrobromic acid, perchloric acid, nitric or thiocyanic acid, sulfuric or phosphoric acids, or organic acids such as formic, acetic, propionic, glycollic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-arninobenzoic, 4hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2- phenoxybenzoic, 2 acetoxybenzoic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, para-toluenesulfonic, naphthalenesulfonic or sulfanilic acid, or methionine, tryptophan, lysine or arginine. The salts may be mono-salts or poly-salts.

contains tertiary amino groups it can be converted by a known method into a quaternary ammonium compound, more especially by reaction with an alkylor benzyl-halide, -sulfate or -sulfonate such, for example, as methyl-, ethyl-, or propylchloride, -bromide or iodide, or with a dialkyl sulfate, for example dimethyl sulfate or diethyl sulfate. Quaternary ammonium salts can also be converted into ammonium hydroxides, for example by the action of freshly precipitated silver oxide on an ammonium halide, or by the action of barium hydroxide solution on an ammonium sulfate; from these ammonium salts other ammonium salts can be prepared by reaction with acids, for example with those mentioned above.

The new compounds are intended to be used as medicaments in the form of pharmaceutical preparations containing them in admixture with an organic or inorganic solid or liquid pharmaceutical vehicle suitable for local, enteral (for example oral) or parenteral administration. Suitable vehicles are substances that do not react with the new compounds, such for example as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, white petro leum jelly, cholesterol or other known medicinal vehicles. The pharmaceutical preparations may be, for example, tablets, drag'ees, capsules, or in liquid form, solutions, suspensions or emulsions. They may be sterilized and/or may contain assistants such as preservatives, stabilisers, wetting agents or emulsifiers, salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. The new compounds may also be used as additives to animal feeds or in veterinary medicine.

The following examples illustrate the invention:

Example I N a s separates out.

l (fldiethylaminoethyl)-6 )xo-lzo dihydropyridazine 3-carboxylic acid hydrazide hydrochloride used as starting material is prepared in the following manner:

15.4 grams of 6-oxo-l:6-dihydropyridazine-3-carboxylic acid methyl ester in 60 cc. of methanol are treated with a solution 2.3 grams of sodium in cc. of methanol and then with 14 grams of chloroethyl-diethylamine in 40 cc. of methanol. The-mixture is, refluxed for 4 hours and allowed to cool, the precipitated crystals are suctioned olf, and the filtrate is evaporated to dryness. The residue is crude 1-(fi-diethylaminoethyl)-6oxo-l:6-dihydropyr1dazine-3-carboxylic acid methyl ester; it is boiled under reflux for one hour in 80 cc. of methanol with 10 grams of hydrazine hydrate, then evaporated in vacuo and the residue is boiled with ether. Evaporation of the ethereal solution yields 1-(fl-diethylaminoethyl)-6-oxo-1:G-dihydropyridazine-3-carboxylic acid hydrazide of the formula CO-NH-NHI t 05H; N-CHgCHgN I CgHs melting at -116" C.

Its hydrochloride, melting at 169-171" C., is obtained bydissolving the base in absolute alcohol and treating the solution with ethanolic hydrochloric acid.

Example 2 A solution of 6.04 grams of l-(fi-morpholinoethyll-fioxo-l G-dihydropyridazine-3-carboxylic acid hydra-zide hydrochloride in 320 cc. of aqueous alcohol of 94% strength is treated with 2.82 grams of S-nitrofuran-Z-aldehyde in 60 cc. of alcohol and the mixture is refluxed for 10 minutes. Upon cooling, l-(p-morpholinoethyD-G-oxofurylidene)-hydrazide hydrochloride of the formula.

. HCl

separates out; it melts at 266-268 C. with decomposition.

1-(fl-morpholinoethyD-6-oxo-l :6-dihydropyridazine 3- carboxyl-ic acid hydrazide hydrochloride used as starting material is prepared in the following manner:

A solution of 2.3 grams of sodium in 200 cc. of methanol is treated with 15.4 grams of 6-oxo-l:6-dihydropyridazine-3-carboxylic acid 'methyl ester and then with a methanolic solution of 16.4 grams of fi-morpholinoethyl-chloride. The mixture is refluxed for 2 hours and then allowed to cool, and the precipitated crystals are suctioned off, and the filtrate is evaporated to dryness. The residue is crude 1-( B-morpholinoethyD-G-oxo-l :6-dihydropyridazine-3-carboxyl-ic acid methyl ester which is boiled in 80 cc. of methanol with 10 grams of hydrazine hydrate for 1% hours under reflux and then evaporated in vacuo. The residue is recrystallized from alcohol, the precipitated crystals are again dissolved in alcohol, and the solution is adjusted with alcoholic hydrochloric acid to pH 6, whereupon l-(p-morpholinoethyl) 6-oxo-pyridazine-3-carboxylic acid hydrazide hydrochloride of the formula I N-CHgCHaN HCl separates out; it melts at 222-224 C.

Example 3 A boiling solution of 4.5 grams of Z-(fl-diethylaminoethylamino)-4-hydroxypyrimidine-5-carboxylici acid hydrazide and 4.5 grams of S-nitrofuran-Z-aldehyde in 200 cc. of ethanol is treated with 50 cc. of 10 N-ethanolic hydrochloric acid. On cooling, crystalline 2-(p-diethylamino-ethylamino)-4 hydroxy-pyrimidine-S carhoxylic acid-N (S-nitro-Z-furfurylidene)-hydrazide hydrochloride of the formula CONH-N=CH-l' N0,

crystallizes in yellow prisms metling at 197199 C.

2-(B-diethylaminoethylaminoy4 hydroxypyrimidine- I S-carboxylic acid hydrazide used as starting material is' which melts at 152-154 after having been recrystallized from methylene chloride+diethyl ether.

A mixture of 10 grams of the aforementioned compound, 50 cc. of anhydrous hydrazine and 25 cc. of alcohol is heated for 7 hours at C., then evaporated to dryness, and the residue is recrystallized from ethanol, to yield 2-(fl-diethylamino-ethylamino)-4 hyd-roxypyrimidine-S- carboxylic acid hydrazide of the formula CONH-NH:

N OH in crystals melting at 198 C.

Example 4 ula ooNHN=cn- JP'NOI CHaN N \N/ NH; HCl 211 0 in the form of crystals melting at 242-245 C.

The 2 (N-methyl-piperazino)-4-amino-pyrimidine-5- carboxylic acid hydrazide used as starting material is prepared as follows:

10 g. of Z-(N-methl-piperazino)-4-amino-5-carbethoxypyrimidine and 20 cc. of anhydrous hydrazine in 20 cc. of ethanol are heated to the boil for 5 hours. On cooling, the 2-(N-methyl-piperazino)-4-amino-pyrimidine-5- carboxylic acid hydrazide of the formula N OONHNHr GHQ-N N-l NH,

crystallizes. Melting point, 217-2l9 C.

Example 5 7.0 g. of S-nitrofuran-Z-aldehyde in 20 cc. of ethanol are added to a solution of 9.5 g. of 2dimet.hylarnino-4- amino-pyrimidine-S-carboxylic acid hydrazide in 100 cc. of an N-solution of hydrogen chloride in ethanol. 2-dimethylamino-4-amino-pyrimidine-S-carboxylic acid N- (5-nitro-2-furfurylidene)-hydrazide-hydrochloride of the formula N CONHN=CHl LNG: Cg; O

/N-\N/ NH, .1101

precipitates immediately. decomposes at 295 C.

The 2-dimethylamino-4-amino-pyrimidine-S-carboxylic acid hydrazide used as starting material is prepared as follows:

10 g. of 2 dimethylamino 4-amino-5-carbethoxypyrimidine and 50 cc. of hydrazine hydrate are heated to the boil for 7 hours. There is obtained in this man- The compound melts and 9 ner the 2-dimethylamino-4-amino-pyrimidine-S-carbqxylic acid hydrazide of the formula C ONHNH: CE:

NKN NH:

in the form of crystals which melt at 237239 C.

Example 6 5.0 g, of Z-n-butylamino4-amino-pyrimidine-5-carboxylic acid hydrazide are dissolved in 50 cc. of an N-alkaline solution of hydrogen chloride. To the resulting solution are added 4.0 g. of 5-nitrofuran-2-aldehyde in 20 cc. of ethanol after which 2-n-butylamino-4-amino-pyrimidine S-carboxylic acid-N-(S-nitro-Ziurfurylidene)-hydrazide-hydrochloride of the formula CONHNH:

precipitates in the form of crystals which melt at 164- What is claimed is:

1. The S-nitro-furyl-(Z)-methylidene-hydrazide of a member selected from the group consisting of acids of the formulae COOH in which R represents a member selected from the group consisting of hydrogen, phenyl, lower alkoxy and lower dialkylamido-,,pyrrolidino-, morpholino-, piperidinoand piperazino-ethoxy, R represents a member selected from the group consisting of hydrogen, lower alkoxy and dilower alkylamino-, pyrrolidino-, morpholino-, piperidind and pip'erazino-ethoxy, R represents a member selected from the group consisting of hydrogen, lower alkyl, phenyl and halogenophenyl, R represents a member selected from the group consisting of phenyl, hydrogen, lower alkyl and halogenophenyl, R represents a member selected from the goup consisting of hydrogen, lower alkyl and dilower alkylamino-, pyrrolidino-, piperidino-, morpholinoand piperazino-ethyl, and of the 2:4-di-amino-pyrimidine- 6-carboxylic acid.

2. Therapeutically acceptable acid addition salts of compounds claimed in claim 1.

3. A member selected from the group consisting of quaternary alkyl and benzyl ammonium salts or the compounds claimed in claim 1.

4. A member selected from the group consisting of compounds of the formula in which formula R stands for a member selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, halogenalkyl and tertiary aminoalkyl radicals, the alkylene chain containing 2 to 4 carbon atoms, and a phenyl, benzyl and pyridyl radical and R represents a member selected from the group consisting of hy-' drogen and hydroxyl, and therapeutically acceptable acid addition salts thereof.

5. A member selected from the group consisting of compounds of the formula and their therapeutically acceptable salts, in which formula N=B stands for a member selected from the group consisting of lower dialkylamino, pyrrolidino, piperidino. morpholino and piperazino groups and n for an integer from 2 to 3.

6. A member selected from the group consisting of the S-nitro-furyl-(Z)-methylidene hydrazide of an acid of the formula R \N' R1 in which R stands for a member selected from the group consisting of hydrogen, amino and hydroxy, and R stands for a member selected from the group consisting of hydrogen and amino, and therapeutically acceptable acid addition salts thereof.

7. A member selected from the group consisting of 1 (B diethylamino ethyl) 6 oxo-lzfi dihyd-ropyridazine 3 carboxylic acid (5' nitro 2' furfurylidene) hydrazide and its therapeutically acceptable acid addition salts.

8. A member selected from the group consisting of 1 (p morpholino ethyl) 6 oxo lz-dihydro pyridazine-3-carboxylic acid-(5'-nitro-2'-furfurylidene)-hydrazide and its therapeutically acceptable acid addition salts.

9. A member selected from the group consisting of 2 (,8 diet-hylamino ethylamino) 4 hydroxy pyrimidine-S-carboxylic 'acid N (5-nitro-2-furfurylidene)-hydrazide and its therapeutically acceptable acid addition salts.

10. A member selected from the group consisting of 2 (N methyl piperazino) 4 amino pyramidine 5- carboxylic acid-(S-nitro-furfurylidene)-hydrazide and its therapeutically acceptable acid addition salts.

11. A member selected from the group consisting of 2 n butylamino 4 amino pyramidine 5 carboxylic acid-(S-nitro-furfurylidene) hydrazide and its therapeutically acceptable acid addition salts.

12. A member selected from the group consisting of 2 dimethylamino 4 amino pyrimidine 5' carboxylic acid-S-(nitro-furfurylidene)-hyclrazide and its therapeutically acceptable acid addition salts.

References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES Ballard et al.; J..Am. Chem. Soc., vol. 64, page 794 (1942).

Carrara et al.: Gazz. Chim. ItaL, vol. 82, pages 652- 661 (1952).

Chemical Abstracts, volume 51, column 15790 (1957) (abstract of Yamaguchi et al., Am. Rept. Shionogi Research Lab., volume 7, pages 123-8 (1957) Chemical Abstracts, volume 52, column 1559 (1958) (abstract of Japanese Patent 349 (1957).

Chemical Abstracts, volume 52, co]. 8212 (1958) (abstract of Japanese Patent 4726 (1957) Chemical Abstract, vol. 51, columns 5897 to 5899 1957) (abstract of Ozawa, Kyoto Daigaku Kekkaka- Kenkyusho Nempo, vol. 4, pages 265-299 (1946)).

Gardner et al.: J. Org. Chem., volume 21, pages 531-2 1956). I

Kakemi et al.: J. of Pharm. Soc. of Japan, vol. 81, pp. 1609 to 1614 (Nov. 1961).

Kushner et al.: J. Am. Chem. Soc., vol. 74, pages 3617 Roba Annales Pharm. Franc., vol. 18, page 519 (1960). Yale et al.: J. Am. Chem. Soc., volume 75, pages 1933- WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,234,219 February 8, 1966 Paul Schmidt et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 10, lines 23 to 3 1, for that portion of the formula reading "-(CH -N=B" read -(CH -N=B Signed and sealed this 7th day of February 1967.

(SEAL) Attest:

ERNEST W. SW'IDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. THE 5-NITRO-FURYL-(2)-METHYLIDENE-HYDROZIDE OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACIDS OF THE FORMULAE
 2. THERAPEUTICALLY ACCEPTABLE ACID ADDITON SALTS OF COMPOUNDS CLAIMED IN CLAIM
 1. 